Abstract

Recent epidemiological and animal model studies indicate that overweight and obese individuals have increased risk not only of type-2 diabetes and cardiovascular diseases but also of various types of cancer. It was suggested that chronic, low-grade inflammation of the adipose tissue, and eventually systemically, is one of the major causes for obesity-associated metabolic abnormalities and cancer, but the trigger, progression and regulation of obesity-induced inflammation and how these processes might influence the development of cancer remain poorly understood. Our laboratory previously discovered a unique population of Foxp3+ CD4+ regulatory T cells (Tregs), with a distinct transcriptome and clonally expanded T cell receptor (TCR) repertoire, residing in the visceral adipose tissue (VAT) of mice and humans. These cells are critical for regulating local inflammation and maintaining systemic insulin sensitivity, but whether they regulate the development of obesity- associated cancers is currently unknown. Moreover, we are still at the early stages of an integrative understanding of the differentiation, trafficking, and expansion of this unique population of VAT cells. Attempting to fill some of these knowledge-gaps, we developed a VAT Treg TCR transgenic (Tg) mouse line, in which Tregs preferentially accumulate in VAT upon recognition of a currently unknown antigen. With this unique tool, we elucidated the life history of VAT Tregs, determined when and where they accumulate and acquired the unique phenotype, identified factors that are important for their homeostasis, and demonstrated their function in suppressing insulin resistance. We are currently in the process of elucidating their function in controlling the obesity- promoted liver inflammation and tumorigenesis. This study will provide foundations for Treg-based immunotherapy against the metabolic syndrome and obesity-associated cancer, while pointing to new cellular and molecular pathways that may constitute potential therapeutic targets.